The U.S. Pat. No. 5,919,926 discloses bicyclic depsipeptides which are produced by fermentation of a specific marine actinomycete (CNB-091) in saltwater-based media. These bicyclic depsipeptides are taught to be useful as anti-biotic and anti-inflammatory agents.
Glucagon is a 29-amino acid peptide hormone produced by the A-cells in the pancreas and is a major counterregulatory hormone to insulin in the maintenance of glucose homeostasis. Insulin promotes the uptake of glucose by cells, especially muscle cells and prevents an excessive breakdown of glycogen stored in liver and muscle. As an antidiabetic hormone essential for lowering blood sugar, insulin is a powerful hypoglycemic agent. In most instances, the actions of glucagon are contrary to those of insulin. Its main function is to stimulate hepatic glucose production. The activated glucagon receptor signals via the cAMP-PKA signalling cascade and increases the rate of glucose de novo synthesis via gluconeogenesis and the liberation of glucose from glycogen stores via glycogenolysis.
Diabetes is a complex disease characterized by hyperglycemia resulting from defect insulin secretion, insulin action, or both. The metabolic complications of diabetes—hyperglycemia and ketosis—are associated with a relative or absolute increase in the ratio of glucagon to insulin. Thus, glucagon is a hyperglycemic factor which causes blood sugar to increase.
Accordingly, a means of treating diabetes is to block the glucagon receptor with a suitable antagonist, thereby inhibiting glucose production by the liver and reducing glucose levels in the patient.
Several publications disclose peptidic and non-peptidic glucagon receptor antagonists (McCormick et al., Curr. Pharm. Des. 7, 1451 (2001) for review). Inhibition of glucagon-stimulated glucose production in humans has been reported for Bay 27-9955 (Petersen et al., Diabetologia 44, 2018 (2001).
It has now been surprisingly discovered that certain bicyclic oligopeptides are highly efficient inhibitors of the glucagon receptor and are therefore of potential use in the treatment or prophylaxis of hyperglycaemia and in particular in the treatment of diabetes mellitus (TypeI and TypeII).
These bicyclic oligopeptides are also indicated to be of potential use for the treatment or prophylaxis of other diseases including IGT (impaired glucose tolerance), insulin resistance syndromes, hyperinsulinemia, hyperlipidemia, dyslipidemia, arteriosclerosis, cardiovascular diseases, hypertension, cardiac hypertrophy, increased renal albumin clearance, glucagonomas, pancreatitis, obesity, gastrointestinal disorders, certain eating disorders and as a therapy to increase gastric acid secretion.